Method and device for delivering aerosolized medicaments

ABSTRACT

A device for accurately delivering aerosolized doses of a medicament disperses a measured amount of drug in a measured volume of carrier gas and transfers the resulting aerosol to a chamber prior to inhalation by a patient. The chamber is filled efficiently with the aerosol, and inhalation by the patient draws the aerosol dose into the lungs. This is followed by the inhalation of atmospheric air that will push the initial dose well into the lung interiors. The apparatus optimally includes a dose regulator, a counter, a clock, a dose memory and a signal to indicate when a dose is ready for inhalation. Optimal chamber designs are disclosed.

The present invention is a continuation of U.S. application Ser. No.08/979,024, filed Nov. 26, 1997; U.S. application Ser. No. 08/576,885,filed Dec. 22, 1995; Ser. No. 08/313,707, filed Sep. 27, 1994; Ser. No.07/910,048, filed Jul. 8, 1992; and a continuation-in-part ofapplication Ser. No. 07/724,915, filed on Jul. 2, 1991, the fulldisclosures of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to a structure and method of administeringprecisely measured doses of a therapeutic by inhalation.

An accurate mechanism for delivering precise doses of aerosol drugs intothe interior of human lungs has been an objective of many workers in theart. One of the most popular aerosol delivery devices is thepropellent-driven metered dose inhaler (MDI), which releases a metereddose of medicine upon each actuation. Although these devices may beuseful for many medicines, only a small variable percentage of themedicine is delivered to the lungs. The high linear speed with which thedosage leaves the device, coupled with incomplete evaporation of thepropellants, causes much of the medicine to impact and stick to the backof the throat. This impacting and sticking creates a local concentrationof drugs much of which is eventually swallowed. In the trade, thisimpact area is called a “hot spot” and can cause localimmuno-suppression and the development of fungal infections withbronchosteriods. With broncodilators, for instance, the swallowed dosecan contribute to unwanted systemic side effects such as tremor andtachycardia.

MDI's also require a degree of coordination between activation andinhalation. Many patients are incapable of this task, especiallyinfants, small children and the elderly. In an effort to overcome someof the above limitations of MDI's, others have interposed “spacers”between the conventional MDI and the patient. The primary function ofthese spacers is to provide extra volume to allow time for increasedpropellent droplet evaporation prior to inhalation and to reduce thevelocity and impact of the medicine at the back of the throat. Althoughspacers do compensate for some of the inadequacies in the conventionalMDI, it has been found that much of the medicine that may haveordinarily been deposit d on the throat remains in the spacer and thetotal dose deposited in the lungs is small. It has been found that onlyapproximately 8% of the medicine reaches the interior of the lung withconventional MDI's. Approximately 13% of the medicine reaches the lungwhen it is equipped with a spacer.

Other workers in the art have attempted to provide a metered dose of amedicant by using dry powder inhalers (DPI). Such devices normally relyon a burst of inspired air that is drawn through the unit. However,these units are disadvantaged in that the force of inspiration variesconsiderably from person to person. Some patients are unable to generatesufficient flow to activate the unit. DPI's have many of thedisadvantages of MDI's in that a large percentage of the medicant isdeposited in the throat because of incomplete particle dispersion andthe impact at the rear of the throat. Although pocket size MDI's andDPI's are very convenient they have disadvantages some of which arecited above.

Other workers in the art have refined aqueous nebulization deliverysystems. Although such systems require a continuous gas compressor,making them less portable than the MDI's and the DPI's, many nebulizersprovide a low velocity aerosol which can be slowly and deeply inhaledinto the lungs. Precision of dosage delivery, however, remains a seriousproblem and it is difficult to determine how much medicament the patienthas received. Most nebulizers operate continuously during inhalation andexhalation. Dosage is dependent on the number and duration of eachbreath. In addition to breath frequency and duration, the flow rate,i.e., the strength of the breath that is taken from a nebulizer caneffect the particle size of the dose inhaled. The patient's inhalationacts as a vacuum pump that reduces the pressure in the nebulizer. Astrong breath can draw larger unwanted particles of medicant out of thenebulizer. A weak breath, on the other hand, will draw insufficientmedicant from the nebulizer.

Electro-mechanical ventilators and devices have also been used in recentyears to deliver inhalable materials to a patient. These devices permitmixing of a nebulized medicant into breathing circuit air only duringpre-set periods of a breathing cycle. An example of this type of machineis the system taught by Edgar et al., in their U.S. Pat. No. 4,677,975,issued in July of 1987 where a nebulizer is connected to a chamber whichin turn is connected to a mouthpiece, an exhaust valve, and an inletvalve. A breath detector and timer are used to deliver nebulizedmaterials to the patient during a portion of the breathing cycle.However, in Edgar and others of this type, the patient's intake strengthcan effect the nebulizer operation with many of the consequencesheretofore mentioned. Moreover, the amount of nebulized materialdelivered in each breath can vary significantly, contributing toinaccurate total dosages. In a modification of Edgar et al. (Elliott, etal. (1987) Australian Paediatr. J. 23:293-297), filling of the chamberwith aerosol is timed to occur during the exhalation phase of thebreathing cycle so that the patient is not inhaling through the deviceduring nebulization. This design, however, requires that the patientmaintain a constantly rhythmic breathing pattern into and out of thedevice, which is inconvenient and can contaminate the device with ovalmicrobes. Moreover, no provision is made on the devices to efficientlycapture the aerosol in the chamber so that as many as 80 breaths or moremust be taken to obtain a dose of medication.

The delivery of therapeutic proteins and polypeptides by inhalationpresents additional problems. Many protein drugs are producedrecombinantly and can thus be very expensive. It is therefore importantthat loss of a protein drug within the delivery device be reduced orpreferably eliminated. That is, substantially all drug initially chargedwithin the device should be aerosolized and delivered to the patientwithout loss within the device or released externally of the device. Theprotein drugs should further be delivered to the patient underconditions which permit their maximum utilization. In particular,protein drugs should be completely dispersed into small particles in thepreferred 1 μm to 5 μm size range which is preferentially delivered tothe alveolar region of the lungs. The amount of protein drug deliveredto the patient in each breath must also be precisely measured so thatthe total dosage of drug can be accurately controlled. Finally, it willbe desirable to permit the delivery of highly concentrated aerosols ofthe protein drug so that the number of breaths required for a givendosage can be reduced, thus increasing accuracy and reducing the totaltime required for administration.

2. Description of the Background Art

U.S. Pat. Nos. 4,926,852 and 4,790,305, describe a type of “spacer” foruse with a metered dose inhaler. The spacer defines a large cylindricalvolume which receives an axially directed burst of drug from apropellant-driven drug supply. U.S. Pat. No. 5,027,806, is animprovement over the '852 and '305 patents, having a conical holdingchamber which receives an axial burst of drug. U.S. Pat. No. 4,624,251,describes a nebulizer connected to a mixing chamber to permit acontinuous recycling of gas through the nebulizer. U.S. Pat. No.4,677,975, is described above. European patent application 347,779describes an expandable spacer for a metered dose inhaler having aone-way valve on the mouthpiece. WO 90/07351 describes a dry powder oralinhaler having a pressurized gas source (a piston pump) which draws ameasured amount of powder into a venturi arrangement.

SUMMARY OF TEE INVENTION

The present invention provides methods and apparatus for producing anaerosolized dose of a medicament for subsequent inhalation by a patient.The method comprises first dispersing a preselected amount of themedicament in a predetermined volume of gas, usually air. The dispersionmay be formed from a liquid, for example by injecting an air streamthrough a liquid reservoir of the drug, or from a dry powder, forexample by drawing the powder into a flowing air stream from a reservoirusing a venturi or other dispersion nozzle. The present invention relieson flowing substantially the entire aerosolized dose into a chamberwhich is initially filled with air and open through a mouthpiece to theambient. The aerosolized dose of medicament flows into the chamber underconditions which result in efficient displacement of the air with theaerosolized material. By “efficient displacement,” it is meant that atleast 40% by weight of the aerosolized material entering the chamberwill remain aerosolized and suspended within the chamber, thus beingavailable for subsequent inhalation through the mouthpiece. It isfurther meant that very little or none of the aerosolized material willescape from the chamber prior to inhalation by the patient. Efficientdisplacement of air and filling of the chamber can be achieved by properdesign of the chamber, as discussed below.

After the aerosolized medicament has been transferred to the chamber,the patient will inhale the entire dose in a single breath. Usually, thetotal volume of aerosolized medicament and air within the chamber willbe substantially less than an average patient's inspiratory capacity,typically being about 100 ml to 750 ml. In this way, the patient canfirst inhale the entire amount of drug present in the dose and continuein the same breath to take in air from the ambient which passes throughthe chamber and which helps drive the medicament further down into thealveolar region of the lungs. Conveniently, the steps of aerosolizingthe medicament, filling the chamber, and inhalation of the chambercontents may be repeated as many times as necessary to provide a desiredtotal dosage of the medicament for the patient.

Apparatus according to the present invention comprise both a dispersiondevice for aerosolizing the medicament, either from a liquid or drypowder formulation of the medicament, and a chamber having an air inletand patient mouthpiece for receiving the aerosolized medicament from thedispersion device. The chamber is designed and connected to thedispersion device in such a way that the aerosolized medicament willflow into the chamber and efficiently displace the internal air volume,as described above. The volume of the chamber will be at least as largeas the maximum expected volume of aerosolized medicament to betransferred from the dispersion device. Usually, the chamber volume willbe greater than the aerosol volume in order to reduce losses through themouthpiece, with exemplary chamber volumes being in the range from 100ml to 750 ml, as described above. The volume of aerosolized medicamentwill usually be in the range from 50 ml to 750 ml when the dispersiondevice is a liquid nebulizer and from 10 ml to 200 ml when thedispersion device is a dry powder disperser, as described in more detailbelow. In order to enhance efficient filling, the chamber willpreferably define an internal flow path so that the entering aerosolizedmedicament will follow the path and displace air within the chamberwithout substantial loss of the medicament through the mouthpiece.Alternatively, the chamber may include a baffle which acts to entrap ahigh velocity aerosol, particularly those associated with dry powderdispersions.

In a preferred aspect, the chamber is generally cylindrical and isconnected to the dispersion device by a tangentially disposed aerosolinlet port located at one end of the cylinder The mouthpiece is thenlocated at the opposite end of the cylinder, and aerosolized medicamentflowing into the chamber will follow a generally vortical flow pathdefined by the internal wall of the chamber. By also providing anambient air inlet at the same end of the cylindrical chamber, thepatient can first inhale the medicament and thereafter breath insubstantial amounts of ambient air, thus sweeping the interior of thechamber to efficiently remove substantially all aerosolized medicamentpresent and help drive the medicament further into the patient's lungs.

In further preferred aspects, the ambient air inlet of the chamber willbe protected, typically through a one-way valve structure which permitsair inflow but blocks aerosol outflow, so that aerosol will not be lostas it enters the chamber. The chamber may also comprise vorticalbaffles, typically in the form of an axially aligned tube or conicalcylinder within the interior of the chamber, to restrict dispersion ofthe aerosol within the chamber and improve delivery efficiency.

In an alternate preferred aspect, the chamber is generally cylindricalwith an axially oriented aerosol inlet port located at one end. Themouthpiece is located at the other end of the cylinder, and an internalbaffle is located between the aerosol inlet and the mouthpiece toprevent direct passage of the aeros 1 to the mouthpiece (which couldresult in loss of medicament well before the chamber has beenefficiently filled). The internal baffle is preferably hemispherical inshape with a concave surface oriented toward the aerosol inlet. Such aconstruction has been found particularly useful in initially containingdry powder dispersions which are often introduced using a high velocity(frequently sonic) gas stream. The chamber further includes a tangentialambient air inlet port disposed in the chamber wall between the aerosolinlet and the internal baffle. By inhaling through the mouthpiece, thepatient is able to establish a vortical flow of ambient air which willsweep the contained aerosol past the baffle and through the mouthpiece.

In yet another aspect of the present invention, the apparatus forproducing aerosolized doses of a medicament comprises the dispersingdevice, means for delivering pressurized gas to the dispersing device,the aerosol chamber, and a controller capable of selectively controllingthe amount of pressurized air delivered to the dispersing device inorder to produce the desired single doses of medicament and deliver saiddoses to the chamber. The controller may include means for timing theactuation of a compressor or means for controlling the amount of gasreleased from a pressurized cylinder, as well as a mechanism forcounting and displaying the number of doses delivered from the chamberduring a particular period of use. Still further, the controller mayinclude a microprocessor and a keypad for inputting information to themicroprocessor.

In exemplary devices, the controller may comprise a timer connected toselectively actuate a valve, such as a solenoid valve, on a gascylinder. Alternatively, the timer may turn on and off an air compressorto regulate the amount of air delivered to the dispersing device. Inportable and hand-held apparatus, the controller may simply be a releasebutton or mechanism that actuates a spring or air driven piston todeliver a specific amount of gas. The controller could also be a meteredvalve which could release a fixed amount of liquid propellant to thedispersing device (in a manner similar to a metered dose inhaler).

The method and the apparatus of the present invention are particularlyeffective for delivering high value drugs, such as polypeptides andproteins, to a patient with minimal loss of the drug in the device.Moreover, the method and device provide for a very accurate measurementand delivery of the doses, while employing relatively simple andreliable equipment. Further advantages of the present invention includethe ability to vary the total dosage delivered, either by controllingthe number of breaths taken or by controlling the amount of medicamentin each breath. Still further, the method and device of the presentinvention permit the delivery of relatively concentrated doses of themedicament in order to reduce the amount of time and number of breathsrequired for the delivery of a total dosage of the medicament,particularly when using dry powder medicament formulations.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic-diagrammatic view of the invention;

FIG. 2 is a diagrammatic cross-sectional view of a holding chamber;

FIG. 3 is a diagrammatic view of the holding chamber;

FIG. 4 is a cross-section along the line 4-4 of FIG. 3;

FIG. 5 is a cross-section along the line 5-5 of FIG. 3;

FIG. 6A-6D are diagrammatic views disclosing the stages of operation;and

FIG. 7 illustrates a venturi nozzle which may be used for dispersing drypowder medicament formulations when used in systems constructed inaccordance with the principles of the present invention;

FIGS. 8-11 illustrate various exemplary chambers which may be used inthe aerosol delivery systems of the present invention.

DESCRIPTION OF THE SPECIFIC EMBODIMENTS

The method and device of the present invention are useful for deliveringa wide variety of medicaments, drugs, biologically active substances,and the like, to a patient's lung, particularly for systemic delivery ofthe medicament or the like. The present invention is particularly usefulfor delivering high value medicaments and drugs, such as proteins andpolypeptides, where efficient delivery and minimum loss are of greatconcern.

The apparatus of the present invention will usually comprise thefollowing basic components: a means for producing a metered volume ofgas, a mixing chamber for generating an aerosol bolus from either aliquid or a powder, a reservoir that contains the medicament, and aholding chamber that efficiently captures the aerosol bolus to maintainthe aerosolized particles in suspension and allow a patient to inhalethe aerosol by a slow, deep inspiration, thereby effectivelydistributing the aerosolized medicament to the distal region of thelungs.

A gas source will usually deliver a preselected volume of gas at greaterthan about 15 psig in order to produce a sonic velocity jet in anaerosol producing region (although sonic velocity is not alwaysnecessary). The pressurized gas is required to efficiently atomize theliquid or break apart the powder producing an aerosol having particlesthat are predominantly 1 to 5 μm in diameter. In addition, the volume ofthe gas bolus must be less than a fraction of a patient's inspiratoryvolume, preferably between 100 to 750 ml. Suitable gas sources include:

-   -   1) an air compressor with a timer to control the operating        period of the compressor (where the timer comprises at least a        portion of the controller discussed hereinafter);    -   2) a compressed gas cylinder with a solenoid valve controlled by        a timer;    -   3) a liquid propellant with a metering valve and an evaporation        chamber;    -   4) a spring piston pump; and    -   5) a pneumatic pump.

The means for producing the aerosol will usually consist of aconstricted orifice that produces a high velocity gas flow to atomize aliquid or break apart powder agglomerates. The present invention isdesigned to be used with a conventional jet nebulizer that operate withairflow rates in the range from 3 to 13 L/min at about 15 psig, with theflow rate depending largely on the nozzle geometry of the nebulizer. Thepresent invention further provides a means of controlling the volume ofair delivered to the nebulizer in order to produce an aerosol bolushaving a specific volume that can be contained in the aerosol holdingchamber. By controlling the gas source to deliver a specific volume ofgas, the system can employ a variety of nebulizers available fromcommercial vendors, such as Marquest, Hudson, Baxter, and PuritanBennett.

The present invention can also operate with a powder jet disperser as ameans of generating an aerosol. A pressurized gas jet produces a highlyturbulent gas flow that serves to break apart powder agglomeratesproducing an aerosol having single particles of the preformed powder. Anexample of a suitable powder/gas mixing chamber is a simple nozzle witha venturi ejector, as shown in FIG. 7. An advantage of this type ofpowder mixer is that the gas flow through the nozzle is only a fractionof the entrained airflow through the venturi. This reduces the aircapacity so that the required volume of gas for dispersing the powdercould be delivered from a small “pocket-sized” gas source.

In addition, the powder dispersing apparatus must produce a pressurepulse having a long enough duration (typically 0.01 to 1 second) toadequately fluidize the powder and efficiently dispense the powder fromthe reservoir. A small diameter nozzle, less than 0.020 inch isacceptable and less than 0.015 inch is preferable, in order to achievean acceptable duration of the pressure pulse at peak pressures exceeding15 psig with a volume of gas that is small enough to be contained in asmall holding chamber.

Referring now to the drawings wherein like numerals indicate like parts,the numeral 10 generally indicates an exemplary apparatus constructed inaccordance with the principles of this invention. The apparatus ispowered by an electrical source 12 that provides energy for acontroller, typically in the form of a microprocessor 18. The presentinvention, however, does not require the use of an electrical or digitalcontroller, so long as some means is provided for supplying preselectedgas volumes for aerosol bolus.

The microprocessor 18 is a general purpose microcontroller unit (MCU)such as that sold by Motorola under their Model Number 68HC05. This unithas on-chip peripheral capabilities and the on-board memory system 30.The on-chip peripheral capability of the Motorola unit includes multipleinput ports, one of which receives the input data from the keypad 13 vialine 16. The microprocessor 18 has a plurality of output ports and itsfunctioning will be more fully understood as the components of theinvention are described.

Keypad 13 has six input keys that are important to performance, namely;13 a, 13 b, 13 c, 13 d, 13 e and 13 f. The volume or amount of eachaerosolized dose is selected by controlling the length of time acompressor 22 is turned on by pressing the “puff size” button 13 a. Thekeypad 12 is programmed so that a first press of button 13 a willdisplay a choice of puff sizes on an LCD 32. Additional pressings of thebutton will select the desired size. A “puff counter actuator” button 13b is pressed which will cause the LCD 32 display “00”. A second press of13 b energizes the air compressor 22 via output line 38 for a 13 a. Thisproduces the first aerosolized dose or bolus of a medicament forinhalation. The LCD display 32 will change from 00 to 01 and the LCDwill increase by one upon each additional activation of the compressor.The patient will continue activating puffs with button 13 b until theprescribed number of puffs have been taken. As these puff events areoccurring, the time and number are stored in memory 30.

T view a record of previous uses of the device, a dosage recall button13 c is pressed which causes LCD 32 to display prior dates, times, puffsizes and number of puff formation events. Successive pressings of thebutton 13 c will enable scrolling of the patient's dosage history.Reversal of scroll direction is accomplished by pressing button 13 d andthen continuing to scroll with 13 c. The button 13 e is a clock/calendarbutton. Pressing the button 13 e causes the LCD 32 to display thecurrent date and time. After the device is used and a series of puffshave been taken, the system will automatically default five minutesafter the last puff to display the actual time and date on the LCDdisplay. Thus, the device is a clock/calendar when not in actual use andduring the use and date or time can be viewed by pressing 13 e.

Air from compressor 22 is communicated to a mixer 40. The mixer 40 maybe a nebulizer, a dry powder dispenser or other type of nebulizer knownto the prior art. When unit 40 is a dry powder dispenser, the compressedair from compressor 22 may optionally be first subjected to coalescingfilter 41 and a desiccant filter 41 a. When unit 40 is a nebulizer, aparticle filter 21 may optionally be placed at the intake 23 of thecompressor to filter out articles before the air is compressed. Ineither case, the medicament or drug will preferably be in the form of asmall particulate, usually having an aerodynamic size in the range from1 μm to 5 μm. It is known that particles in this size range are mostefficiently delivered to the alveolar regions of the lungs.

An exemplary dry powder venturi nozzle 200 is illustrated in FIG. 7. Theventuri nozzle 200 includes a side port 202 which receives an initialcharge of powder medicament M, typically a lyophilized protein orpolypeptide. The powder is drawn into dispersion chamber 204 at thepoint where nozzle orifice 206 introduces a high velocity gas stream inthe direction of arrow 208. The high velocity gas stream will resultfrom pressurized gas or air in plenum 210, which may be provided by aseparate air compressor 22 (FIG. 1) or an air or gas cylinder (notillustrated). The low pressure caused by the air or gas stream will drawthe powder continuously into the dispersion chamber 204 whereagglomerates of the powder are broken into smaller sizes within thepreferred 1 μm to 5 μm range by the turbulent shear effect in thechamber.

In any event, unit 40 is of a type that will nebulize or mix a definedamount of medicant with the preselected amount of compressed airreceived from compressor 22. This defined amount, referred to as adosage or bolus, flows into a chamber 42 via the conduit 39. The chamber42 is transparent, typically having a glass, transparent plastic, orsimilar wall 44.

A critical aspect of the present invention is the ability to transferthe aerosolized medicament from the mixer 40 into the chamber 42 withoutsubstantial loss of medicament through the mouthpiece or within thechamber. Such losses will be minimized so that at least about 40% byweight of the medicament delivered to the chamber will remainaerosolized and suspended within the chamber after the entire volume hasbeen transferred. Preferably, at least about 55% will remain suspended,more preferable at least about 70%. Such low losses are desirable sincethe total amount of drug which may be introduced into the chamber foreach transfer is maximized, and thus the amount which may be inhaled ineach breath by a patient is increased. Additionally, even small lossesof high valued drugs, such as proteins and polypeptides, can becomesignificant over time. Still further, the ability to deliver aconcentrated aerosol dispersion of drug into the chamber will increasethe concentration of drug delivered to the patient with each breath.Such high concentration dosages are preferable since they can reduce thetotal number of breaths necessary to deliver a prescribed amount ofdrug, thus increasing the total amount of time required for thetreatment.

Loss of aerosolized medicament can be reduced by minimizing mixingbetween the aerosolized medicament and the displaced air as the chamberis being filled. Minimum mixing between the aerosol transferred from themixing chamber 40 and the displaced air within chamber 42 can beenhanced by properly designing the chamber 42 as well as the inlet flowgeometry of the aerosol into the chamber. Particularly preferredgeometries are illustrated in FIGS. 2-5 and 8-11, as described in moredetail hereinbelow.

A light 50 and/or an audible signal 52 will alert the user that a puffis ready to be withdrawn from chamber 42 when the compressor 22 shutsdown. At this point in time, the aerosolized bolus of medicine is quitevisible. From the holding chamber 42 the medicament is inhaled by thepatient via a conduit 45 through a mouthpiece 46 or in the case of smallchildren or infants , a face mask 48. A one-way check valve 47 isdisposed across conduit 45 to prevent exhalation into chamber 42. Thesignals 50 and 52 are set to begin immediately after operation of thecompressor 22 ceases. The cessation of the compressor sound will alsoalert the patient that bolus formation is complete. This sequence isrepeated for each bolus and the microprocessor 18 will count and recordeach instance of compressor activation so that the prescribed number ofaerosolized boluses have been administered. The number of boluses, theirhour and date and their size (time f compressor use), are recorded,stored and recallable at a future time f r display on LCD 32 by pressingdosage history button 13 c.

One embodiment of the aerosol holding chamber 42 is best seen incross-section in FIG. 2. The chamber 42 is comprised basically of a top54, the previously mentioned transparent sidewall 44 and a bottom 58.The chamber 42 is equipped with an aerosol intake stub fitting 60 at thelower portion thereof. The chamber top is equipped with an inhalationstub 62. Also at the bottom 58 is an atmospheric intake stub 64. Thestubs are formed to accept conventional connector fittings 70, 72 and 74respectively. The fittings connect the conduits 45, 96 and 80 to thestub-fillings 60, 62 and 64. The fittings permit the ready interchangeof chambers having different volumetric capacities.

Disposed in a conduit 39, between unit 40 and chamber 42, is a valve 80that is opened before use of the device and closed between uses. Thevalve 80 serves as a vapor lock to prevent evaporation of fluid fromunit 40 when the nebulizer is not in use. Valve 80 can be controlled byhand like a stop-clock, or it may be electronically controlled by theMCU 18 so that upon pressing the puff counter/actuator button 13 b,valve 80 opens and then closes by default if the machine is not used fora set period. Disposed across inhale line 45 is a one-way check valve47. A one-way check valve 94 is also disposed across the air intakeconduit 96.

Particularly preferred chamber geometries are illustrated in FIGS. 8-11.Chamber 100 in FIG. 8 comprises a cylindrical body 102 with a tangentialaerosol inlet port 104. The tangential aerosol inlet port 104 will beconnected to a suitable aerosol dispersing device, usually either anebulizer or a dry powder device (as described above), preferably anebulizer, and the aerosol will enter and assume a vortical flowpattern, as indicated by arrows 106. The entry of the aerosol willdisplace air initially present in the chamber 100 through mouthpiece108. Usually, but not necessarily, the chamber 100 will be orientedvertically with the mouthpiece at the top. After the entire aerosolbolus has entered the chamber 100 (typically only partially filling thechamber leaving a “buffer” of air near the mouthpiece 108), the patientwill inhale through the mouthpiece 108, drawing in ambient air throughambient air inlet 110, thus sweeping the chamber of the aerosolizedmedicament. Ambient air inlet 110 will usually have a one-way valve,such as a flap or diaphragm valve (not illustrated) in order to preventloss of aerosol as the aerosol is introduced through port 104.

Chamber 120 in FIG. 9 is similar to chamber 100, except that an inlettube 122 extends into the chamber interior, forming a vortical baffle.Apertures 124 are disposed about the inlet tube 122 to permit entry ofair as the patient inhales through mouthpiece 126. Ambient air inlet 128is similar to inlet 104 in FIG. 8.

A horizontally disposed chamber 140 is illustrated in FIG. 10. Chamber140 includes both a tangential aerosol inlet 142 and tangentialmouthpiece 144. Thus, aerosolized medicament will enter through theinlet 142 and move horizontally across the chamber interior toward themouthpiece 144. An advantage of this design is that the aerosolparticles will tend to drop below the level of the mouthpiece 144 asthey cross the chamber. Thus, loss of the medicament through themouthpiece 144 will be minimized. Ambient air inlet 146 is provided topermit air infusion as the patient inhales through the mouthpiece 144.

A preferred chamber 150 for use with dry powder dispersion devices, suchas venturi nozzle 200 in FIG. 7, is illustrated in FIG. 1A. The chamber150 will generally be maintained with its axis oriented vertically, withan aerosol inlet 152 at its lower end and a mouthpiece 154 at its upperend. The chamber 150 further includes an internal baffle 156 which issuspended from a rod 158 attached to the upper end of the chamber. Thebaffle 156 is preferably hemispherical, with its open or concave endoriented downwardly toward aerosol inlet 152. The purpose of the baffle156 is to contain the initial plume of aerosol created by the highvelocity air or gas stream. The hemispherical design is preferred sinceit will redirect the initial flow of aerosol back downward, creating arecirculation as indicated by the arrows in FIG. 11B. Other geometriesfor the baffle, including flat plates, perforated plates, cylinders,cones, and the like, might also find use, with the primary requirementbeing that the baffle design be able to provide an initial containmentzone within the chamber.

After an aerosolized dose or bolus of medicament has been introduced tothe chamber 150, the patient will inhale through the mouthpiece 154,drawing ambient air in through ambient air inlet 158. The inlet 158includes a one-way flap or diaphragm valve 160 which permits the inflowof air but prevents the initial loss of medicament as the aerosolizeddose enters through the inlet 152. The ambient air inlet 158 is disposedtangentially on the chamber 150, and entry of ambient air through theinlet cause a vortical (as illustrated in FIG. 11C) which will cause thesuspended medicament particles to move radically outward (due to theinduced cyclone effect) and be carried upward by the airflow through theannular region 162 between the periphery of the baffle 156 and theinterior wall of the chamber 150.

Surprisingly, the design of chamber 150 has been found to be able toreceive a volume of aerosolized medicament greater than the chambervolume without substantial loss of medicament through the mouthpiece. Itis believe that the baffle 156 can act as a “concentrator,” whichcontains the medicament particles in the region below the baffle whilepermitting air flow through the annular region 162. Such concentrationis achieved while still maintaining the aerosolized particles insuspension and with the ability to subsequently transfer the medicamentparticles to the mouthpiece by introducing a vortical flow of ambientair through inlet 158, as described above.

In operation, the patient or medical attendant will ready the device byoperating the puff size button 13 a. Button 13 b is pressed a secondtime to energize compressor 22 and a pre-selected amount of air under aconstant pressure is delivered to unit 40 for mixing or nebulizing toform the first puff. The medicament begins filling the chamber 42 fromthe bottom (FIG. 6A) through valve 80 and stub fitting 60 and a cloudy,observable “puff” is formed as seen in FIG. 6B. During this timeinterval, valve 94 is closed.

After the vessel or chamber 42 is filled, the signals 50 and 52 areactivated for several seconds by the timer function of themicroprocessor 18. The duration of both signals will be preset in thecontrol program 24. As a breath is taken, valves 47 and 94 will open topermit the puff to enter the lungs and to permit additional atmosphericair to enter the chamber from the bottom through conduit 96.

The volumetric size of chamber 42 is only a fraction of the capacity ofthe patients' lungs usually being from 200 ml to 1000 ml, typicallybeing about 500 ml. Inhalation by the patient will thus initially drawthe entire dose of medicament into the lungs. The volume of aerosoltransferred to the chamber will typically be about 10 ml to 750 ml, andthe air that enters through valve 94 can thus act as an air piston todrive the smaller volume of aerosol deep into the user's lungs. Thebottom to top filling and vertical flow pattern result in a minimum ofdispersion and dilution of the aerosol. Moreover, the sweeping ofchamber 50 with air after each inhalation helps assure substantiallycomplete delivery of the drug to the patient.

The atmospheric or pure air and the medicament bolus, each moves fromthe chamber 42 through the one-way check valve 47 into the patient'smouth via the conduit 45. A mask 48 with a one-way exhalation port isused for patients that require same. A one-way valve 47 may be used toprevent the patient from accidentally exhaling into the chamber 42.

FIG. 6A-6D show illustrations of the sequence of bolus generation andwithdrawal from the aerosol holding chamber 42.

The following examples are offered by way of illustration, not by way oflimitation.

Experimental Equipment

Air supply—a nitrogen cylinder with a regulator, a needle valve, apressure gauge, and a solenoid valve that is operated with a timer witha resolution of 0.01 second.

Jet Nebulizer—Rapid-Flo™, (Allersearch, Vt. Victoria, Australia)

Powder Disperser—A venturi (as illustrated in FIG. 7) having a 0.013inch diameter jet nozzle.

Aerosol Holding Chambers—Fabricated from plastic with internal volumesof 750 ml. Design 1—3-inch cylindrical chamber with spherical top andbottom and one 90°-port at the base, one 45°-port at the top and onetangential port on the side (as illustrated in FIG. 8). Design 2—3-inchcylindrical chamber with spherical top and bottom and a 1 inchcylindrical spacer located axially along the center of the chamber.Three ports—one 90°-port at the base, one 45°-port at the top and onetangential port on the side (as illustrated in FIG. 9). Design 3—3-inchcylindrical chamber with spherical top and bottom; a 2½ inchhemispherical baffle held in the center of the chamber with a rod. Thebaffle was located approximately 2inches above the base of the chamber.Three ports—aerosol intake: 90°-port at the base, mouthpiece: 45°-portat the top and makeup air intake: tangential port on the side (asillustrated in FIG. 11). Design 4—3-inch cylindrical chamber withspherical top and bottom; a 2½ inch hemispherical baffle located 2¾inches above the base on a c ne (as illustrated in FIG. 11).

Methods

The four aerosol chamber designs were tested using either the jetnebulizer or the powder dispenser. Design 1 was tested using either the90°-port at the base for the aerosol intake or the tangential port asthe aerosol intake.

The total airflow through the apparatus, the aerosol generator and theholding chamber, was measured with a rotameter connected to themouthpiece of the holding chamber. The flow was set to the desired ratewith the needle valve. The pressure was maintained above 15 psig toensure sonic velocity in the nozzle of the aerosol generator.

Once the airflow was set, the sample was loaded into the aerosolgenerator. The operating period was set on the timer. A toggle switch onthe timer opened the solenoid valve sending air through the aerosolgenerator and producing the aerosol. We observed the distribution of theaerosol in the holding chamber and could observe when the aerosol beganto flow out of the chamber. The maximum length of time that the aerosolgenerator could be operated and still capture all of the aerosol in theholding chamber was determined by adjusting the operating period on thetimer and repeating the steps listed above. The aerosol dose volume wascalculated from the flow rate and the time the solenoid was open. Avacuum line was connected to the holding chamber following an actuationto clear the chamber of the aerosol before actuating again.

A 0.9% saline solution was used in testing the different holding chamberconfigurations with a Rapid-Flow nebulizer. The nebulizer was operatedat flow rate of 19 L/min which resulted in 24 psig across the jet of thenebulizer.

The powder disperser was tested at a pressure of 30 psig which resultedin a flow rate of 10.4 L/min through the apparatus. Approximately 5 mgof a test powder, prepared by spray drying a solution of mannitol andbovine serum albumin, was loaded into the venturi intake and thesolenoid valve was actuated. We checked for powder remaining in theventuri intake to determine whether there was an adequate air supply todisperse the powder. The particle size distribution measured from thechamber using an Aerosizer (API, Hadley, Mass.) particle size analyzershowed that the aerosol contained particles between 1 and 4 μm indiameter.

Results

Results comparing the different chamber designs for containing theaerosol are reported in Table 1. The maximum volume of the aerosolcontained by the chamber was calculated from the maximum operating timeand the total airflow. The proportion of the aerosol volume to thevolume of the chamber given in the % Chamber Volume column is a way ofcomparing the effectiveness of the different chamber designs forcontaining the aerosol. The air volume needed to disperse 5 mg of powdercould be efficiently captured in all of the chamber configurationstested. The designs that induced a vertical airflow pattern in thechamber retained a larger volume of aerosol. TABLE 2 Aerosol CaptureEfficiency for several Holding Chamber Designs Nebulizer PowderDisperser % of Increase % of Increase Cham- Aerosol Chamber over AerosolChamber over ber Volume Volume base Volume Volume base De- 348 mL 45.8%— 69. mL 9.24% — sign 1 bottom fill De- 665 mL 86.7% 1.94 95.3 mL 12.7%1.38 sign 1 tangen- tial fill De- 728 mL 97.1% 2.12 104 mL 13.9% 2.50sign 2 center baffle De- 950 mL  127% 2.77 164 mL 21.9% 2.37 sign 3hemi- sphere baffle De- 855 mL  114% 2.49 161 mL 21.5% 2.33 sign 4

Conclusions

An aerosol holding chamber can be designed that efficiently captures ameasured volume of aeros 1. A chamber designed to induce vorticalairflow pattern in the chamber by a tangential aerosol intake or usingbaffles distributes the aerosol more evenly in the chamber without lossfrom the mouthpiece. For use with a nebulizer, a vortical airflowproduces a higher concentration of medicament in the chamber so that aneffective dose could be taken with fewer puffs. The results with thepowder disperser show that the vortical flow and properly designedbaffles are effective in containing a powder aerosol produced by aturbulent jet.

It should be understood that the preferred embodiments of the presentinvention have been disclosed by way of example and that othermodifications may occur to those skilled in the art without departingfrom the scope and spirit of the appended claims.

1. (canceled)
 2. Au apparatus for producing aerosolized medicament, theapparatus comprising: a reservoir containing a powder medicament to beaerosolized, the powder medicament comprising a protein or polypeptide;and a chamber comprising an inlet and a mouthpiece, wherein gas may flowinto the chamber through the inlet and may flow out of the chamberthrough the mouthpiece and wherein the flow of gas aerosolizes thepowder medicament, wherein at least 40 percent by weight of the powdermedicament is suspended by the gas in the chamber for delivery rough themouthpiece.
 3. An apparatus according to claim 2 wherein the chambervolume is from 100 ml to 750 ml.
 4. An apparatus according to claim 2further comprising a source of compressed gas, wherein the compressedgas may be released if the source of compressed gas to cause the flow ofgas to aerosolize the medicament.
 5. An apparatus according to claim 2wherein the chamber is adapted contain the aerosolized medicament forsubsequent delivery to a patient during a patient's inhalation.
 6. Anapparatus according to claim 2 wherein the chamber is cylindrical.
 7. Anapparatus according to claim 2 when the aerosolizes medicament comprisessmall particles of medicament, the particles being sized to bedeliverable to the alveolar regions of the lungs of a patient.
 8. Anapparatus according to claim 7 wherein the particles are predominantly 1to 5 micrometers in diameter.
 9. An apparatus according to claim 2wherein at least 55 percent by weight of the powder medicament issuspended by the gas in the chamber for delivery through die mouthpiece.10. An apparatus according to claim 2 wherein at least 70 percent byweight of the powder medicament is suspended by the gas in the chamberfor delivery through the mouthpiece.
 11. An apparatus for producingaerosolized medicament, the apparatus comprising: a reservoir containinga powder medicament to be aerosolized, the powder medicament comprisinga protein or polypeptide; and a chamber comprising an inlet and amouthpiece, wherein gas may flow into the chamber through the inlet andmay flow out of the chamber through the mouthpiece and wherein the flowof gas aerosolizes the powder medicament, wherein the volume of theaerosolized medicament is from 9.24 percent to 21.5 percent of thevolume of the chamber.
 12. An apparatus according to claim 11 whereinthe chamber volume is from 100 ml to 750 ml.
 13. An apparatus accordingto claim 11 further comprising a source of compressed gas, wherein thecompressed gas may be released from the source of compressed gas tocause the flow of gas to aerosolize the medicament.
 14. An apparatusaccording to claim 11 wherein the chamber is adapted contain theaerosolized medicament for subsequent delivery to a patient during apatient's inhalation.
 15. An apparatus according to claim 11 wherein thechamber is cylindrical.
 16. An apparatus according to claim 11 whereinthe aerosolizes medicament comprises small particles of medicament, theparticles being sized to be deliverable to the alveolar regions of thelungs of a patient.
 17. An apparatus according to claim 16 wherein theparticles are predominately 1 to 5 micrometers in diameter.
 18. Anapparatus according to claim 11 wherein at least 40 percent by weight ofthe powder medicament is suspended by the gas in the chamber fordelivery through the mouthpiece.
 19. An apparatus according to claim 11where at least 70 percent by weight of the powder medicament issuspended by the gas in the chamber for delivery trough the mouthpiece.